Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver disease in the United States, and accounts for the majority of cryptogenic cirrhosis. NASH is associated with the "metabolic syndrome", which includes insulin-resistance, obesity, and dyslipidemia. In addition, recent evidence indicates that there is a strong genetic component for the susceptibility and progression of steatohepatitis. Unfortunately, the genetic factors responsible for the pathogenesis of NASH remain poorly understood. NASH is a polygenic disease, and Quantitative Trait Loci (QTL) analysis is a widely utilized genetic technique that can be applied to murine models in order to determine the chromosomal loci responsible for the expression of complex traits and polygenic diseases. Feeding mice a methionine- choline deficient (MCD) diet serves as an animal model for progressive, fibrosing steatohepatitis. Thus, Specific Aim 1 will employ a methionine-choline deficient (MCD) diet to identify steatohepatitis-susceptible and steatohepatitis-resistant strains of mice;and utilize QTL analysis to identify the genetic loci associated with steatohepatitis. NASH is also associated with the metabolic syndrome, and feeding mice a High Fat, High Calorie (HFHC) diet is a well-characterized model for obesity, the metabolic syndrome, and hepatic steatosis. However, the molecular mechanisms of hepatic injury in mice fed a HFHC diet remain poorly understood. Thus, Specific Aim 2 will employ a High Fat, High Calorie (HFHC) diet to determine the genetic loci and signaling pathways that account for the hepatic disease susceptibility. Candidate genes that are important for the pathogenesis of nonalcoholic fatty liver disorders can be identified from hepatic inflammatory and metabolic signaling pathways;particularly if they are differentially expressed in disease-sensitive and disease-resistant mice. Similarly, genes associated with NASH in human genetic studies can also serve as candidate genes. Therefore, Specific Aim 3 will employ a candidate gene approach to identify causative genes that are important in the pathogenesis of steatohepatitis and steatosis. This application utilizes two complementary models of hepatic steatosis and steatohepatitis, and state-of-the-art genetic and molecular biological techniques, in order to enhance our understanding of the pathogenesis of steatohepatitis. This enhanced understanding of the pathophysiologic mechanisms responsible for steatohepatitis will allow for the design of rational therapies for this hepatic disease that affects millions of Americans. PUBLIC HEALTH RELEVANCE: Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver disease in the United States, although the pathogenesis remains poorly understood. These specific aims will employ two complementary models of steatosis and steatohepatitis, and utilize state-of-the-art genetic and molecular biological techniques, in order to enhance our understanding of the pathogenesis of steatohepatitis and susceptibility to NASH. An understanding of the pathophysiologic mechanisms responsible for the development and progression of NASH will allow for the design of rational therapies of this common hepatic disease that affects millions of Americans.